NM_018965.4:c.40G>T

Variant names:

• chr6-41163043-C-A
• rs386834143
• NM_018965.4:c.40G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PM2 PP3_Strong PP5_Moderate

The NM_018965.4(TREM2):​c.40G>T​(p.Glu14*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TREM2 NM_018965.4 stop_gained, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.02

Genes affected

TREM2 (HGNC:17761): (triggering receptor expressed on myeloid cells 2) This gene encodes a membrane protein that forms a receptor signaling complex with the TYRO protein tyrosine kinase binding protein. The encoded protein functions in immune response and may be involved in chronic inflammation by triggering the production of constitutive inflammatory cytokines. Defects in this gene are a cause of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2012]

ENSG00000290034 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 6-41163043-C-A is Pathogenic according to our data. Variant chr6-41163043-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 56724.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-41163043-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4	c.40G>T	p.Glu14*	stop_gained, splice_region_variant	Exon 1 of 5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2	c.40G>T	p.Glu14*	stop_gained, splice_region_variant	Exon 1 of 4		NP_001258750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREM2	ENST00000373113.8	c.40G>T	p.Glu14*	stop_gained, splice_region_variant	Exon 1 of 5	1	NM_018965.4	ENSP00000362205.3
TREM2	ENST00000373122.8	c.40G>T	p.Glu14*	stop_gained, splice_region_variant	Exon 1 of 5	1		ENSP00000362214.4
TREM2	ENST00000338469.3	c.40G>T	p.Glu14*	stop_gained, splice_region_variant	Exon 1 of 4	1		ENSP00000342651.4
ENSG00000290034	ENST00000702590.1	n.364+7480C>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 Pathogenic:1

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 Pathogenic:1

Oct 17, 2019

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Pathogenic for Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 , autosomal recessive. The following ACMG Tag(s) were applied: PM2, PS3, PVS1-Strong, PM3-Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	49
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.79
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386834143; hg19: chr6-41130781;